Like Left 4 Dead, the sequel involves the aftermath of an apocalyptic pandemic.There has been an outbreak of a rabies-like pathogen that causes infected humans to behave like zombies.The four survivors have to fight their way through the hordes of infected, using safehouses along the way to rest and recover, in order to reach extraction points.

Left 4 Dead 2 is set in the Southern United States, starting in Savannah, Georgia and ending in New Orleans, Louisiana.Left 4 Dead 2 introduces four new survivors, whose backstory will again be provided through dialogue.Unlike the first game where there was no significant story development, Left 4 Dead 2 will feature a story arc.

Several new features are introduced, such as new types of infected, melee weapons, and a story-arc that connects each of the game's five campaigns together.